OVERALL DESCRIPTION (adapted from application): Studies with attenuated macrophage tropic SIV/17E have led the applicants to hypothesize that the best HIV vaccine is live attenuated, macrophage-tropic, and mucosally delivered. They propose to prove this hypothesis and to explore mechanism(s) whereby protection can be enhanced and broadened, and to identify correlates of protection to aid in human trials. In Specific Aim 1, the investigators plan to identify differences in immune responses associated with systemic versus rectal immunization with T-tropic (SIV239 delta nef) versus M-tropic (SIV/17E) vaccines. They will also compare the temporal emergence of neutralizing antibody, antibody avidity, cellular immune responses, and CD8+ T cell suppressor activity in the peripheral blood, and secretory IgA, CD8+ suppressor activity and CTL in the intestinal lamina propria in monkeys infected intravenously or intra- rectally with the two vaccines. In these studies, monkeys will be challenged rectally, then intravenously, with SIV/DeltaB670. In Specific Aim 2, the applicants will identify mechanism(s) employed by SIV in evading protective immunity. Recombinant infectious clones carrying fragments of variant env sequences from the escape mutant will be constructed by Dr. Clements (Project 4). These will be used to infect monkeys to determine the role of these sequences in T- and B-cell immunity, viral tropism, and virulence. Monkeys will be challenged with the parental variant to identify the specific epitope(s) involved in immune escape. In Specific Aim 3, monkeys will be infected with SIV/17E and SIV/239 expression TH1 and TH2 cytokines (gm-CSF, IL-12, IL-5, and the B7 co-stimulatory molecule) to determine whether site-directed expression of cytokines can augment protective immunity either mucosally or systematically. In Specific Aim 4, attenuated SHIV vaccines specific for different HIV clades, will be constructed by Dr. Luciw (Core C) using requirement show optimal for SIV, will be evaluated to both expand the understanding of HIV and to determine the breadth of the protective responses possible.